CD4+CD25+ Immunoregulatory T Cells

CD4+CD25+ immunoregulatory T cells play a pivotal role in preventing organ-specific autoimmune diseases and in tolerance induction to allogeneic organ transplants. We investigated whether these cells could also control graft-versus-host disease (GVHD), the main complication after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we show that the few CD4+CD25+ T cells naturally present in the transplant regulate GVHD because their removal from the graft dramatically accelerates this disease. Furthermore, the addition of freshly isolated CD4+CD25+ T cells at time of grafting significantly delays or even prevents GVHD. Ex vivo–expanded CD4+CD25+ regulatory T cells obtained after stimulation by allogeneic recipient-type antigen-presenting cells can also modulate GVHD. Thus, CD4+CD25+ regulatory T cells represent a new therapeutic tool for controlling GVHD in allogeneic HSCT. More generally, these results outline the tremendous potential of regulatory T cells as therapeutics.

• Publication year

  2002

• Venue

  Journal of Experimental Medicine

• Publication date

  2002-08-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20020090PMID 12163568PMCID 2193933
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Control of T cell activation by CD4+CD25+ suppressor T cells.

  2003cited by this paper
• Control of T‐cell activation by CD4+ CD25+ suppressor T cells

  2001cited by this paper
• IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo1

  2001cited by this paper
• Cell Contact–Dependent Immunosuppression by Cd4+Cd25+Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β

  2001cited by this paper
• Cd4+Cd25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade

  2001cited by this paper
• Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function

  2001cited by this paper
• Regulatory T Cells Induced by 1α,25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance1

  2001cited by this paper
• Suppressor T cells – they’re back and critical for regulation of autoimmunity!

  2001cited by this paper
• Identification and Functional Characterization of Human Cd4+Cd25+ T Cells with Regulatory Properties Isolated from Peripheral Blood

  2001cited by this paper
• Suppressor Effector Function of CD4+CD25+ Immunoregulatory T Cells Is Antigen Nonspecific

  2000cited by this paper
• CD4+CD25+ regulatory T cells down‐regulate co‐stimulatory molecules on antigen‐presenting cells

  2000influential reference
• B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes.

  2000cited by this paper
• CD25 Is a Marker for CD4+ Thymocytes That Prevent Autoimmune Diabetes in Rats, But Peripheral T Cells with This Function Are Found in Both CD25+ and CD25− Subpopulations1

  2000cited by this paper
• Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4

  2000cited by this paper
• Regulatory T cells: key controllers of immunologic self-tolerance.

  2000cited by this paper
• Immunological Defects after Suicide Gene Therapy of Experimental Graft-versus-Host Disease

  1999cited by this paper
• An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation

  1999cited by this paper
• Regulatory T Cells in the Control of Autoimmunity: the Essential Role of  Transforming Growth Factor β and Interleukin 4 in the Prevention of Autoimmune Thyroiditis in Rats by Peripheral CD4+CD45RC− Cells and CD4+CD8− Thymocytes

  1999cited by this paper
• Would suicide gene therapy solve the 'T-cell dilemma' of allogeneic bone marrow transplantation?

  1999cited by this paper
• CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells.

  1998cited by this paper
• Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.

  1998cited by this paper
• Clinical Practice of Stem-Cell Transplantation

  1998cited by this paper
• Thymic aging and T‐cell regeneration

  1997cited by this paper
• A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells

  1996cited by this paper
• Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

  1995cited by this paper
• Graft-versus-leukemia reactions after bone marrow transplantation.

  1990cited by this paper
• Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial.

  1989cited by this paper
• Down-regulation of homing receptors after T cell activation.

  1988cited by this paper
• Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts.

  1985cited by this paper
• Bone marrow transplantation.

  1977cited by this paper
• Bone-marrow transplantation (second of two parts).

  1975cited by this paper

• Longitudinal analysis identifies bystander-activated innate cytotoxic CD8+ T cells as predictors and therapeutic biomarkers for acute graft-versus-host disease

  2026cites this paper
• Tregs in allogeneic hematopoietic stem cell transplantation (allo-HSCT): Suppressing GVHD While Preserving GVL.

  2025cites this paper
• Buprenorphine's Effect on the Human Immune System and Inflammation

  2025cites this paper
• Isolation and Expansion of Clinical Grade T Regulatory Cells for GvHD Prophylaxis

  2025cites this paper
• Development of a humanized mouse model of graft-versus-host disease to assess human regulatory T cell function

  2025cites this paper
• Cellular therapies for the prevention and treatment of acute graft-versus-host disease.

  2025cites this paper
• Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease

  2024cites this paper
• Polyclonally Derived Alloantigen-Specific T Regulatory Cells Exhibit Target-Specific Suppression and Capture MHC Class II from Dendritic Cells.

  2024cites this paper
• Clinical grade multiparametric cell sorting and gene-marking of regulatory T cells.

  2024cites this paper
• CD74 supports accumulation and function of regulatory T cells in tumors

  2024cites this paper
• The role of interleukin-2 in graft-versus-host disease pathogenesis, prevention and therapy.

  2024cites this paper
• Influence of FOXP3 single-nucleotide polymorphism after allogeneic hematopoietic stem cell transplantation

  2024cites this paper
• Pathophysiology and preclinical relevance of experimental graft-versus-host disease in humanized mice

  2024cites this paper
• Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation.

  2024cites this paper
• Engineered Treg cells: The heir to the throne of immunotherapy.

  2023cites this paper
• Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy

  2023cites this paper
• Microenvironment in Acute Myeloid Leukemia: focus on senescence mechanisms, therapeutic interactions and future directions.

  2023cites this paper
• Editorial: Regulatory T cells in graft versus host disease

  2023cites this paper
• Regulatory T cells in autoimmune kidney diseases and transplantation

  2023cites this paper
• TCF-1 negatively regulates the suppressive ability of canonical and non-canonical Tregs.

  2023cites this paper
• Metabolic Disruption Induced by mTOR Signaling Pathway Inhibition in Regulatory T-Cell Expansion for Clinical Application

  2023cites this paper
• Combining Treg Therapy With Donor Bone Marrow Transplantation: Experimental Progress and Clinical Perspective

  2023cites this paper
• The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8^+ T-cell immunity

  2023cites this paper
• Treg-targeted IL-2/anti-IL-2 complex controls graft-versus-host disease and supports anti-tumor effect in allogeneic hematopoietic stem cell transplantation

  2023cites this paper
• Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases

  2023cites this paper
• Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy

  2023cites this paper
• Graft versus Leukemia in 2023.

  2023cites this paper
• TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation

  2022cites this paper
• Milestones in acute GVHD pathophysiology

  2022cites this paper
• Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells

  2022cites this paper
• Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

  2022cites this paper
• Donor Genetic Predisposition to High Interleukin-10 Production Appears Protective against Acute Graft-Versus-Host Disease

  2022cites this paper
• Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses

  2022cites this paper
• Immune-Related Genes for Predicting Future Kidney Graft Loss: A Study Based on GEO Database

  2022cites this paper
• T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

  2022cites this paper
• High proportion of terminally differentiated regulatory T cells after allogeneic hematopoietic stem cell transplantation

  2021cites this paper
• Maturation and Phenotypic Heterogeneity of Human CD4+ Regulatory T Cells From Birth to Adulthood and After Allogeneic Stem Cell Transplantation

  2021cites this paper
• Exploiting Single-Cell Tools in Gene and Cell Therapy

  2021cites this paper
• Interleukin‐2‐inducible T‐cell kinase (Itk) signaling regulates potent noncanonical regulatory T cells

  2021cites this paper
• Chimeric Antigen Receptors and Regulatory T Cells: The Potential for HLA-Specific Immunosuppression in Transplantation

  2021cites this paper
• CD28 Superagonist D665-mediated activation of mouse regulatory T cells maintains their phenotype without loss of suppressive quality.

  2021cites this paper
• The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

  2021cites this paper
• Regulatory T Cells in GVHD Therapy

  2021cites this paper
• A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD

  2021cites this paper
• Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

  2021cites this paper
• Mobilized Multipotent Hematopoietic Progenitors Promote Expansion and Survival of Allogeneic Tregs and Protect Against Graft Versus Host Disease

  2021cites this paper
• CD4+CD8+ T-Lymphocytes in Xenogeneic and Human Graft-versus-Host Disease

  2020cites this paper
• Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies

  2020cites this paper
• CLINICAL-GRADE EXPANDED TREGS ARE ENRICHED WITH HIGHLY SUPPRESSIVE CELLS PRODUCING IL-10, GRANZYME B AND IL-35.

  2020cites this paper
• New insights into the basic biology of acute graft-versus-host-disease.

  2020cites this paper
• Regulatory T cell therapy: Current and future design perspectives.

  2020cites this paper
• New insights into the basic biology of acute graft-versus-host-disease.

  2020cites this paper
• Infectious tolerance. What are we missing?

  2020cites this paper
• Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

  2020cites this paper
• Dissecting the biology of allogeneic HSCT to enhance the GvT effect whilst minimizing GvHD

  2020cites this paper
• Comparison of rapamycin and methylprednisolone for treating inflammatory muscle disease in a murine model of experimental autoimmune myositis

  2020cites this paper
• Heparin affects the induction of regulatory T cells independent of anti‐coagulant activity and suppresses allogeneic immune responses

  2020cites this paper
• How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft-Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation

  2020cites this paper
• Ex vivo expansion of regulatory T cells from long-term Belatacept-treated kidney transplant patients restores their phenotype and suppressive function but not their FOXP3 TSDR demethylation status.

  2020cites this paper
• Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells

  2020cites this paper
• Induction of CD4+CD25+ Regulatory T Cells from In Vitro Grown Human Mononuclear Cells by Sparteine Sulfate and Harpagoside

  2020cites this paper
• High expression of granzyme B in conventional CD4+ T cells is associated with increased relapses after allogeneic stem cells transplantation in patients with hematological malignancies.

  2020cites this paper
• Regulatory T Cells in the Tumor Microenvironment.

  2020cites this paper
• Role of Myeloid-Derived Suppressor Cells and Regulatory T-Cells in the Tuberculous Granuloma

  2019cites this paper
• Chimeric antigen receptor costimulation domains modulate human regulatory T cell function.

  2019cites this paper
• Next-generation regulatory T cell therapy

  2019cites this paper
• Therapeutic use of regulatory T cells for graft‐versus‐host disease

  2019influential citation
• Immune regulation in hematopoietic cell transplantation

  2019cites this paper
• Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease

  2019cites this paper
• The mechanistic study behind suppression of GVHD while retaining GVL activities by myeloid-derived suppressor cells.

  2019cites this paper
• Peripherally-Derived Regulatory T Cells in Mouse Autoimmune Diabetes

  2019cites this paper
• Advances in understanding the pathogenesis of graft‐versus‐host disease

  2019cites this paper
• Single-cell Analysis of CAR-T Cell Activation Reveals A Mixed TH1/TH2 Response Independent of Differentiation

  2019cites this paper
• The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

  2019cites this paper
• Cord blood 2.0: state of the art and future directions in transplant medicine

  2019cites this paper
• Immune Regulatory Cell Biology and Clinical Applications to Prevent or Treat Acute Graft-Versus-Host Disease

  2019cites this paper
• In vivo administration of recombinant BTNL2-Fc fusion protein ameliorates graft-versus-host disease in mice.

  2019cites this paper
• Overview of the Immune Biology of Allogeneic HSCT

  2019cites this paper
• Allogeneic haematopoietic stem cell transplantation

  2019cites this paper
• T-Regulatory Cells In Tumor Progression And Therapy

  2019cites this paper
• T-Cell Costimulation and Coinhibition in Graft-Versus-Host Disease and Graft-Versus-Leukemia Effect

  2019cites this paper
• In Vivo Imaging of GVHD and GVL

  2019cites this paper
• CMAR_A_228887 10731..10747

  2019cites this paper
• Foxp3+ Regulatory and Conventional CD4+ T Cells Display Similarly High Frequencies of Alloantigen-Reactive Cells

  2019cites this paper
• Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4+CD25+ regulatory T cells

  2019cites this paper
• Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells

  2019cites this paper
• Treg cell-based therapies: challenges and perspectives

  2019cites this paper
• CD4+FOXP3+ Regulatory T Cell Therapies in HLA Haploidentical Hematopoietic Transplantation

  2019cites this paper
• Regulatory roles of IL-10–producing human follicular T cells

  2019cites this paper
• The role of regulatory T cells in graft-versus-host disease management

  2019cites this paper
• Thymus-Derived CD4+CD25+ FOXP3+ Regulatory T Cells in GVHD

  2019cites this paper
• Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology

  2018cites this paper
• Cell banking for regulatory T cell-based therapy: strategies to overcome the impact of cryopreservation on the Treg viability and phenotype

  2018cites this paper
• Ocular Surface and Tear Film Characteristics in a Sclerodermatous Chronic Graft-Versus-Host Disease Mouse Model

  2018cites this paper
• Correlation Between Stem and Progenitor Cells Number and Immune Response in Patients After Allogeneic Kidney Transplant

  2018cites this paper
• The ex vivo toll-like receptor 7 tolerance induction in donor lymphocytes prevents murine acute graft-versus-host disease.

  2018cites this paper
• Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies

  2018cites this paper
• Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia

  2018cites this paper
• Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier.

  2018cites this paper
• Regulatory T cells in the treatment of disease

  2018cites this paper